Kay See Tan

Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Patients With Stage I Non–Small-Cell Lung Cancer: A Competing Risks Analysis

Purpose To perform competing risks analysis and determine short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who had undergone resection for stage I non-small-cell lung cancer (NSCLC). Patients and Methods Of 5,371 consecutive patients who had undergone curative-intent resection of primary lung cancer at our institution (2000 to 2011), 2,186 with pathologic stage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were included in the analysis, specifically, Charlson comorbidity index, predicted postoperative (ppo) diffusing capacity of the lung for carbon monoxide, and ppo forced expiratory volume in 1 second. Cause-specific mortality analysis was performed with competing risks analysis. Results Of 2,186 patients, 1,532 (70.1%) were ≥ 65 years of age, including 638 (29.2%) ≥ 75 years of age. In patients < 65, 65 to 74, and ≥ 75 years of age, 5-year lung cancer-specific cumulative incidence of death (CID) was 7.5%, 10.7%, and 13.2%, respectively (overall, 10.4%); noncancer-specific CID was 1.8%, 4.9%, and 9.0%, respectively (overall, 5.3%). In patients ≥ 65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer-specific CID; the higher noncancer-specific, early-phase mortality was enhanced in patients ≥ 75 years of age than in those 65 to 74 years of age. Multivariable analysis showed that low ppo diffusing capacity of lung for carbon monoxide was an independent predictor of severe morbidity ( P < .001), 1-year mortality ( P < .001), and noncancer-specific mortality ( P < .001), whereas low ppo forced expiratory volume in 1 second was an independent predictor of lung cancer-specific mortality ( P = .002). Conclusion In patients who undergo curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with an increasing impact as patient age increases.

Spread through Air Spaces (STAS) Is an Independent Predictor of Recurrence and Lung Cancer–Specific Death in Squamous Cell Carcinoma

Introduction: Spread through air spaces (STAS) is a recently recognized pattern of invasion in lung adenocarcinoma; however, it has not yet been characterized in squamous cell carcinoma (SCC). Methods: We reviewed 445 resected stage I to III lung SCCs and investigated the clinical significance of STAS. Cumulative incidence of recurrence and lung cancer–specific death were evaluated by competing risks analyses and overall survival by Cox models. Results: Of the total 445 patients, 336 (76%) were older than 65 years. Among the 273 patients who died, 91 (33%) died of lung cancer whereas the remaining ones died of competing events or unknown cause. STAS was observed in 132 patients (30%) and the frequency increased with stage. The cumulative incidences of any, distant, and locoregional recurrence as well as lung cancer–specific death were significantly higher in patients with STAS compared with in those without STAS, whereas there was no statistically significant difference in overall survival. In multivariable models for any recurrence and lung cancer–specific death, STAS was an independent predictor for both outcomes (p = 0.034 and 0.016, respectively). Conclusion: STAS was present in one‐third of resected lung SCCs. In competing risks analysis in a cohort in which three‐fourths of the patients were elderly, STAS was associated with lung cancer–specific outcomes. Our findings suggest that STAS is one of the most prognostically significant histologic findings in lung SCC.

Pulmonary metastasectomy with therapeutic intent for soft-tissue sarcoma

Objective: Soft‐tissue sarcoma is a heterogeneous disease that frequently includes the development of pulmonary metastases. The purpose of this study is to determine factors associated with improved survival among patients with soft‐tissue sarcoma to help guide selection for pulmonary metastasectomy. Methods: We reviewed a prospectively maintained database and identified 803 patients who underwent pulmonary metastasectomy for metastatic soft‐tissue sarcoma between September 1991 and June 2014; of these, 539 patients undergoing 760 therapeutic‐intent pulmonary metastasectomies were included. Clinicopathologic variables and characteristics of treatment were examined. The outcomes of interest were overall survival and disease‐free survival. Survival was estimated with the Kaplan‐Meier method and compared between variables with the log‐rank test. Factors associated with hazard of death and recurrence were identified via the use of univariable and multivariable Cox proportional hazards models. Results: Median overall survival was 33.2 months (95% confidence interval, 29.9–37.1), and median disease‐free survival was 6.8 months (95% confidence interval, 6.0–8.0). In multivariable analyses, leiomyosarcoma histologic subtype (P = .007), primary tumor size ≤10 cm (P = .006), increasing time from primary tumor resection to development of metastases (P < .001), solitary lung metastasis (P = .001), and minimally invasive resection (P = .023) were associated with lower hazard of death. Disease‐free interval ≥1 year (P = .002), and 1 pulmonary metastasis (P < .001) were associated with lower hazard of disease recurrence. Conclusions: In a large single‐institution study, primary tumor histologic subtype and size, numbers of pulmonary metastases, disease‐free interval, and selection for minimally invasive resection are associated with increased survival in patients undergoing pulmonary metastasectomy for soft‐tissue sarcoma.

Postinduction positron emission tomography assessment of N2 nodes is not associated with ypN2 disease or overall survival in stage IIIA non-small cell lung cancer.

OBJECTIVE Induction therapy is often recommended for patients with clinical stage IIIA-N2 (cIIIA/pN2) lung cancer. We examined whether postinduction positron emission tomography (PET) scans were associated with ypN2 disease and survival of patients with cIIIA/pN2 disease. METHODS We performed a retrospective review of a prospectively maintained database to identify patients with cIIIA/pN2 non-small cell lung cancer treated with induction chemotherapy followed by surgery between January 2007 and December 2012. The primary aim was the association between postinduction PET avidity and ypN2 status; the secondary aims were overall survival, disease-free survival, and recurrence. RESULTS Persistent pathologic N2 disease was present in 61% of patients (61 out of 100). PET N2-negative disease increased from 7% (6 out of 92) before induction therapy to 47% (36 out of 77) afterward. The sensitivity, specificity, and accuracy of postinduction PET for identification of ypN2 disease were 59%, 55%, and 57%, respectively. Logistic regression analysis indicated that postinduction PET N2 status was not associated with ypN2 disease. Of the 39 patients with both pre- and postinduction PET N2-avidity, 25 (64%) had ypN2 disease. The 5-year overall survival was 40% for ypN2 disease versus 38% for N2-persistent disease (P = .936); the 5-year overall survival was 43% for postinduction PET N2-negative disease versus 39% for N2-avid disease (P = .251). The 5-year disease-free survival was 34% for ypN2-negative disease versus 9% for N2-persistent disease (P = .079). CONCLUSIONS Postinduction PET avidity for N2 nodes is not associated with ypN2 disease, overall survival, or disease-free survival in patients undergoing induction chemotherapy for stage IIIA/pN2 disease.

Cell cycle progression score is a marker for five-year lung cancer-specific mortality risk in patients with resected stage I lung adenocarcinoma

Purpose The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes. Methods Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer–specific mortality as the primary outcome. Results In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer–specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14–2.24; P=0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer–specific mortality (HR=1.77; 95% CI, 1.18–2.66; P=0.006). Five-year lung cancer–specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P<0.001). In patients with intermediate-grade lung ADC of acinar and papillary subtypes, high mPS was associated with worse 5-year lung cancer–specific survival (P<0.001 and 0.015, respectively), compared with low mPS. Conclusion This study validates CCP score and mPS as independent prognostic markers for lung cancer–specific mortality and provides quantitative risk assessment, independent of known high-risk features, for stage I lung ADC patients treated with surgery alone.

The RNA-editing enzyme ADAR promotes lung adenocarcinoma migration and invasion by stabilizing FAK

Editing of FAK mRNA by the enzyme ADAR in lung adenocarcinoma cells promotes migration and invasion. Metastatic edits to FAK Drugs that inhibit cell migration pathways, such as that mediated by the kinase FAK, may prevent metastasis and improve long-term survival in cancer patients. Amin et al. found that the RNA-editing enzyme ADAR supports the activity of FAK. In lung adenocarcinoma cells, ADAR bound to and edited FAK mRNA in a manner that improved its stability, thus increasing the abundance of FAK protein and enhancing the migration of these cells. High ADAR expression was a poor prognostic indicator in patients. These findings suggest that inhibiting FAK may be therapeutic in patients with ADAR-positive lung adenocarcinoma. Large-scale, genome-wide studies report that RNA binding proteins are altered in cancers, but it is unclear how these proteins control tumor progression. We found that the RNA-editing protein ADAR (adenosine deaminase acting on double-stranded RNA) acted as a facilitator of lung adenocarcinoma (LUAD) progression through its ability to stabilize transcripts encoding focal adhesion kinase (FAK). In samples from 802 stage I LUAD patients, increased abundance of ADAR at both the mRNA and protein level correlated with tumor recurrence. Knocking down ADAR in LUAD cells suppressed their mesenchymal properties, migration, and invasion in culture. Analysis of gene expression patterns in LUAD cells identified ADAR-associated enrichment of a subset of genes involved in cell migration pathways; among these, FAK is the most notable gene whose expression was increased in the presence of ADAR. Molecular analyses revealed that ADAR posttranscriptionally increased FAK protein abundance by binding to the FAK transcript and editing a specific intronic site that resulted in the increased stabilization of FAK mRNA. Pharmacological inhibition of FAK blocked ADAR-induced invasiveness of LUAD cells, suggesting a potential therapeutic application for LUAD that has a high abundance of ADAR.

Definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by surgery for stage II to III esophageal squamous cell carcinoma

Objective: Definitive chemoradiotherapy (CRT) remains the most commonly used treatment for locally advanced esophageal squamous cell carcinoma (SCC), because of perceptions that esophagectomy offers an unclear survival advantage. We compare recurrence, overall survival (OS), and disease‐free survival (DFS) in patients treated with definitive CRT or neoadjuvant CRT followed by surgery (trimodality). Methods: This was a retrospective cohort study of patients with stage II and III SCC of the middle and distal esophagus in patients who completed CRT. Treatment groups were matched (1:1) on covariates using a propensity score‐matching approach. The effect of trimodality treatment, compared with definitive CRT, on OS, DFS, and site‐specific recurrence was evaluated as a time‐dependent variable and analyzed using Cox regression with a gamma frailty term for matched units. Results: We included 232 patients treated between 2000 and 2016: 124 (53%) with definitive CRT and 108 (47%) with trimodality. Trimodality was used less frequently over time (61% before 2009 and 29% after 2009; P < .0001). After matching, each group contained 56 patients. Median OS and DFS were 3.1 and 1.8 years for trimodality versus 2.3 and 1.0 years for CRT. Surgery was independently associated with improved OS (hazard ratio, 0.57; 95% confidence interval, 0.34–0.97; P = .039) and DFS (hazard ratio, 0.51; 95% confidence interval, 0.32–0.83; P = .007). Conclusions: CRT followed by surgery might decrease local recurrence and increase DFS and OS in patients with esophageal SCC. Until better tools to select patients with pathological complete response are available, surgery should remain an integral component of the treatment of locally advanced esophageal SCC.

BRMS1 Expression in Surgically Resected Lung Adenocarcinoma Predicts Future Metastases and Is Associated with a Poor Prognosis

Introduction Expression of breast cancer metastasis suppressor 1 gene (BRMS1) is decreased in NSCLC cells and tumors. We hypothesized that intratumoral breast cancer metastasis suppressor 1 (BRMS1) expression is associated with lung adenocarcinoma (LUAD) histologic subtypes and overall survival (OS) and disease‐free survival (DFS) in patients undergoing resection for early‐stage LUAD. Methods Patients (N = 1030) who underwent complete resection for LUAD with tissue available for histologic evaluation were identified. Tissue microarrays were constructed, and immunostaining was performed and scored for intensity of BRMS1 expression. OS and DFS were estimated (by the Kaplan‐Meier method) and compared between groups (by the log‐rank test), stratified by stage. Hazard ratios (HRs) for hazard of death and recurrence were estimated using univariable and multivariable Cox proportional hazards models. OS and DFS nomograms were created, and model performance was examined. Results Intratumoral BRMS1 expression was high in 632 patients (61%) and low in 398 (39%). Low BRMS1 expression was associated with higher pathologic T stage (p = 0.001), larger tumor size (p ≤ 0.0001), greater lymphatic (p = 0.032) and vascular (p = 0.001) invasion, LUAD histologic subtype (p = 0.001), and intermediate and high architectural tumor grade (p = 0.003). Low BRMS1 expression was an independent predictor of worse OS (HR = 1.35, 95% confidence interval: 1.10–1.65, p = 0.004) and DFS (HR = 1.27, 95% confidence interval: 1.05–1.54, p = 0.012). OS and DFS nomograms showed excellent predictive performance based on discrimination and calibration. Conclusions Among patients with surgically resected LUAD, OS and DFS were significantly worse in cases with low intratumoral BRMS1 expression. Our findings suggest that BRMS1 is an independent biomarker with prognostic significance in surgically resected LUAD.

Factors associated with distant recurrence following R0 lobectomy for pN0 lung adenocarcinoma

Objective: We investigated factors associated with distant recurrence, disease‐free survival (DFS), and overall survival (OS) following R0 lobectomy for pathologic node‐negative (pN0) lung adenocarcinoma. Methods: We performed a retrospective analysis of a prospectively maintained database of patients with pT1‐3N0M0 non–small cell lung cancer. Exclusion criteria included metachronous lung cancer, sublobar/incomplete resection, nonadenocarcinoma histology, and induction/adjuvant therapy. The primary outcome was distant recurrence; secondary outcomes were DFS and OS. Associations between variables and outcomes were assessed by Fine–Gray competing‐risk regression for distant recurrence and Cox proportional hazard models for DFS and OS. Results: Of 2392 patients identified with pT1‐3N0M0 lung adenocarcinoma, 893 met the inclusion criteria. Median follow‐up was 35.0 months (range, 0.1‐202 months). Thirteen percent of patients developed recurrence (n = 115), of which 86% (n = 99) were distant. The 5‐year cumulative incidence of distant recurrence was 14% (95% confidence interval [CI], 11%‐17%). On multivariable analysis, pT2a (hazard ratio [HR], 2.84; 95% CI, 1.56‐5.16; P = .001) and pT2b/3 (HR, 6.53; 95% CI, 3.17‐13.5; P < .001) tumors were associated with distant recurrence. Recent surgery was associated with decreased distant recurrence (HR, 0.43; 95% CI, 0.20‐0.91; P = .028), and lymphovascular invasion was strongly associated with distant recurrence (HR, 1.62; 95% CI, 1.00‐2.63; P = .05). DFS was independently associated with pT stage (P < .001) and lymphovascular invasion (P = .004). Conclusions: In patients undergoing R0 lobectomy with pN0 lung adenocarcinoma, pT stage and lymphovascular invasion were associated with distant recurrence and decreased DFS. These observations support the inclusion of these patients in future clinical trials investigating adjuvant targeted and immunotherapies.

Outcomes Following Neoadjuvant or Adjuvant Chemotherapy for cT2-4N0-1 Non-Small Cell Lung Cancer: A Propensity-Matched Analysis

Objective Comparative survival between neoadjuvant chemotherapy and adjuvant chemotherapy for patients with cT2‐4N0‐1M0 non–small cell lung cancer has not been extensively studied. Methods Patients with cT2‐4N0‐1M0 non–small cell lung cancer who received platinum‐based chemotherapy were retrospectively identified. Exclusion criteria included stage IV disease, induction radiotherapy, and targeted therapy. The primary end point was disease‐free survival. Secondary end points were overall survival, chemotherapy tolerance, and ability of Response Evaluation Criteria In Solid Tumors response to predict survival. Survival was estimated using the Kaplan–Meier method, compared using the log‐rank test and Cox proportional hazards models, and stratified using matched pairs after propensity score matching. Results In total, 330 patients met the inclusion criteria (n = 92/group after propensity‐score matching; median follow‐up, 42 months). Five‐year disease‐free survival was 49% (95% confidence interval, 39‐61) for neoadjuvant chemotherapy versus 48% (95% confidence interval, 38‐61) for adjuvant chemotherapy (P = .70). On multivariable analysis, disease‐free survival was not associated with neoadjuvant chemotherapy or adjuvant chemotherapy (hazard ratio, 1.1; 95% confidence interval, 0.64‐1.90; P = .737), nor was overall survival (hazard ratio, 1.21; 95% confidence interval, 0.63‐2.30; P = .572). The neoadjuvant chemotherapy group was more likely to receive full doses and cycles of chemotherapy (P = .014/0.005) and had fewer grade 3 or greater toxicities (P = .001). Response Evaluation Criteria In Solid Tumors response to neoadjuvant chemotherapy was associated with disease‐free survival (P = .035); 15% of patients receiving neoadjuvant chemotherapy (14/92) had a major pathologic response. Conclusions Timing of chemotherapy, before or after surgery, is not associated with an improvement in overall or disease‐free survival among patients with cT2‐4N0‐1M0 non–small cell lung cancer who undergo complete surgical resection.